Delta 9-Tetrahydrocannabinol (Delta 9-THC) is the primary psychoactive compound in marihuana extracts. The mechanism of action of Delta 9-THC at the cellular level is unclear. The long- term objective of the proposed research is to determine how neurons respond to Delta 9-THC. The methodology unique to this project is the use of cloned neuroblastoma cells (N18TG2) in culture as a model system for neurons. Delta 9-THC inhibits adenylate cyclase in these cells via a receptor-regulated G protein. The specific aims of this proposal are to: 1) characterize structure-activity relationships in neuroblastoma membranes using cannabimimetic analgetic compounds; 2) determine if cyclic AMP is altered by cannabimimetic drugs in target sites in the rat brain; 3) develop a ligand binding assay to characterize the receptor in neuroblastoma and brain membranes; and 4) determine if cannabimimetic drugs cause significant effects on adenylate cyclase by altering membrane fluidity. Cannabimetic drugs are potentially useful as anti-glaucoma, analgesic, anti-emetic or anti-convulsant agents. Further, Delta 9-THC is one of the most popular drugs of abuse (smoked marihuana). In spite of this, very little is known concerning the way these drugs alter neurons in the brain. The proposed studies will elucidate at least one mechanism of action of cannabimimetic compounds (inhibition of adenylate cyclase), and may uncover other mechanisms which may or may not be receptor-mediated. Further investigations can define the complex interaction of neurons that respond to Delta 9-THC with other neurons in the brain.